title: Ceacam1 deletion causes vascular alterations in large vessels.
abstract: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) promotes hepatic insulin clearance and endothelial survival. However, its role in the morphology of macrovessels remains unknown. Mice lacking Ceacam1 (Cc1-/-) exhibit hyperinsulinemia, which causes insulin resistance and fatty liver. With increasing evidence of an association among hyperinsulinemia, fatty liver disease, and atherosclerosis, we investigated whether Cc1-/- exhibited vascular lesions in atherogenic-prone aortae. Histological analysis revealed impaired endothelial integrity with restricted fat deposition and aortic plaque-like lesions in Cc1-/- aortae, likely owing to their limited lipidemia. Immunohistochemical analysis indicated macrophage deposition, and in vitro studies showed increased leukocyte adhesion to aortic wall, mediated in part by elevation in vascular cell adhesion molecule 1 levels. Basal aortic eNOS protein and NO content were reduced, in parallel with reduced Akt/eNOS and Akt/Foxo1 phosphorylation. Ligand-induced vasorelaxation was compromised in aortic rings. Increased NADPH oxidase activity and plasma 8-isoprostane levels revealed oxidative stress and lipid peroxidation in Cc1-/- aortae. siRNA-mediated CEACAM1 knockdown in bovine aortic endothelial cells adversely affected insulin's stimulation of IRS-1/PI 3-kinase/Akt/eNOS activation by increasing IRS-1 binding to SHP2 phosphatase. This demonstrates that CEACAM1 regulates both endothelial cell autonomous and nonautonomous mechanisms involved in vascular morphology and NO production in aortae. Systemic factors such as hyperinsulinemia could contribute to the pathogenesis of these vascular abnormalities. Cc1-/- mice provide a first in vivo demonstration of distinct CEACAM1-dependent hepatic insulin clearance linking hepatic to macrovascular abnormalities.
authors.affiliation: Center for Diabetes and Endocrine Research, College of Medicine and life Sciences, University of Toledo, Health Science Campus, Toledo, Ohio;
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Najjar
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Ledford
authors.forename: Simon L
authors.initials: SL
authors.lastname: Abdallah
authors.forename: Alexander
authors.initials: A
authors.lastname: Paus
authors.forename: Lucia
authors.initials: L
authors.lastname: Russo
authors.forename: Meenakshi K
authors.initials: MK
authors.lastname: Kaw
authors.forename: Sadeesh K
authors.initials: SK
authors.lastname: Ramakrishnan
authors.forename: Harrison T
authors.initials: HT
authors.lastname: Muturi
authors.forename: Christian K
authors.initials: CK
authors.lastname: Raphael
authors.forename: Sumona Ghosh
authors.initials: SG
authors.lastname: Lester
authors.forename: Garrett
authors.initials: G
authors.lastname: Heinrich
authors.forename: Sandrine V
authors.initials: SV
authors.lastname: Pierre
authors.forename: Ralf
authors.initials: R
authors.lastname: Benndorf
authors.forename: Veronika
authors.initials: V
authors.lastname: Kleff
authors.forename: Ayad A
authors.initials: AA
authors.lastname: Jaffa
authors.forename: Emile
authors.initials: E
authors.lastname: Lévy
authors.forename: Guillermo
authors.initials: G
authors.lastname: Vazquez
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Goldberg
authors.forename: Nicole
authors.initials: N
authors.lastname: Beauchemin
authors.forename: Rosario
authors.initials: R
authors.lastname: Scalia
authors.forename: Süleyman
authors.initials: S
authors.lastname: Ergün
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001013:Aorta, Thoracic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D002272:Carcinoembryonic Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002417:Cattle; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D058226:Plaque, Atherosclerotic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D034622:RNA Interference; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C069847:CD66 antigens; D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D015815:Cell Adhesion Molecules; D019010:Vascular Cell Adhesion Molecule-1; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse
keywords: NEFA; fatty liver disease; metabolic syndrome; obesity